Journal of Pediatric Gastroenterology & Nutrition:
Lactobacillus GG Administered in Oral Rehydration Solution to Children with Acute Diarrhea: A Multicenter European Trial
Guandalini, Stefano; Pensabene, Licia; Zikri, Mona Abu*; Dias, Jorge Amil†; Casali, Luigi Gobio‡; Hoekstra, Hans§; Kolacek, Sanja÷; Massar, Karin§; Micetic–Turk, Dusanka¶; Papadopoulou, Alexandra#; de Sousa, Jaime Salazar**; Sandhu, Bhupinder††; Szajewska, Hanna‡‡; Weizman, Zvi§§
Unitá di Pediatria, Università di Catanzaro, Italy; *Cairo University Children's Hospital, El Cairo, Egypt; †Faculdade de Medicina, Hospital S. João, Porto, Portugal; ‡Divisione di Pediatria Ospedale Civile di Mantova, Italy; §Department of Pediatrics, Hertogenbosch, The Netherlands; ÷Children's Hospital, Zagreb, Croatia; ¶Department. of Pediatrics Teaching Hospital, Maribor, Slovenia; #“P & A Kyriakou” Children's Hospital, Athens, Greece; **Department of Pediatrics Hospital de Santa Maria, Lisbon, Portugal; ††Bristol Royal Hospital for Sick Children, Bristol, United Kingdom; ‡‡The Medical University of Warsaw, Poland; and §§Soroka Medical Center, Ben-Gurion University, Beer-Sheva, Israel
Received February 15, 1999;
revised August 10, 1999; accepted August 13, 1999.
Address correspondence and reprint requests to Dr. Stefano Guandalini, University of Chicago, Department of Pediatrics, 5841 S. Maryland Avenue, Chicago, IL 60637-1470.
Background: The probiotic Lactobacillus GG is effective in promoting a more rapid recovery of acute, watery diarrhea in children with rotavirus enteritis. Very limited information is available, however, on the potential role of such agents in nonrotaviral diarrheal episodes. Furthermore, no evidence is available concerning the efficacy of Lactobacillus GG administered in the oral rehydration solution during oral rehydration therapy. A multicenter trial was conducted to evaluate the efficacy of Lactobacillus GG administered in the oral rehydration solution to patients with acute-onset diarrhea of all causes.
Methods: Children 1 month to 3 years of age with acute-onset diarrhea were enrolled in a double-blind, placebo-controlled investigation. Patients were randomly allocated to group A, receiving oral rehydration solution plus placebo, or group B, receiving the same preparation but with a live preparation of Lactobacillus GG (at least 1010 CFU/250 ml). After rehydration in the first 4 to 6 hours, patients were offered their usual feedings plus free access to the same solution until diarrhea stopped.
Results: One hundred forty children were enrolled in group A, and 147 in group B. There were no differences at admission between the groups in age, sex, previous types of feeding, previous duration of diarrhea, use of antibiotics, weight, height, weight–height percentile, prevalence of fever, overall status, degree of dehydration, and percentage of in-versus outpatients. Duration of diarrhea after enrollment was 71.9 ± 35.8 hours in group A versus 58.3 ± 27.6 hours in group B (mean ± SD;P = 0.03). In rotavirus-positive children, diarrhea lasted 76.6 ± 41.6 hours in group A versus 56.2 ± 16.9 hours in groups B (P < 0.008). Diarrhea lasted longer than 7 days in 10.7% of group A versus 2.7% of group B patients (P < 0.01). Hospital stays were significantly shorter in group B than in group A.
Conclusions: Administering oral rehydration solution containing Lactobacillus GG to children with acute diarrhea is safe and results in shorter duration of diarrhea, less chance of a protracted course, and faster discharge from the hospital.
Acute-onset diarrheal episodes are still a common occurrence worldwide. Agents that could prove to be safe and effective in reducing the duration of the episode or in preventing its possible evolution toward a protracted course would be a valuable therapeutic resource. In recent years it has been shown that the probiotic Lactobacillus GG (ATC 53103), a strain known to colonize the human gut, is effective in promoting a more rapid recovery of acute, watery diarrhea due to rotavirus in children. Scant evidence is available on the potential role of such an agent in nonrotaviral (i.e., mainly bacterial) diarrheal episodes. It is also not known whether Lactobacillus GG might help in preventing a prolonged diarrheal course or in reducing the duration of hospital stay for inpatients. Furthermore, the probiotic has been used only as a supplement given after completion of rehydration in previous studies, whereas it is conceivable that its use in the early phase of treatment (i.e., during oral rehydration) might be even more beneficial, by allowing a more rapid interaction of the organism with the acutely diseased mucosa. To answer these questions, the Working Group on Acute Diarrhea of the European Society for Paediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) launched a 1-year study in 1996 that involved 11 centers in 10 countries.
MATERIALS AND METHODS
We enrolled weaned children 1 month to 3 years of age who had had more than four movements per day of liquid or semiliquid stools for 1 to 5 days. Local ethics committees of the participating hospitals, where appropriate, approved the study. Exclusion criteria were previous use of all kinds of probiotics, underlying chronic untreated small bowel disease, inflammatory bowel diseases, and any other underlying chronic disease or immune-suppressive condition or treatment. The investigation was double blind and placebo controlled. After informed consent was received from parents, patients were randomly allocated to either group A or group B. Group A children received a solution prepared in each center by dissolving the content of sachet A in 250 ml of water. When reconstituted, this resulted in a hypotonic oral rehydration solution (ORS), formulated according to the ESPGHAN ad hoc committee recommendations (1), plus placebo. Children in group B were given a solution also prepared in each center by dissolving the content of sachet B into aliquots of 250 ml of water. This resulted in an identical ORS (see Table 1 for composition) but one that contained a preparation of live Lactobacillus GG (at least 1010 CFU/250 ml). The sachets of Lactobacillus GG for both groups of patients were kindly provided to each participating center by Dicofarm SpA (Rome, Italy) and kept refrigerated until use. All the patients were rehydrated during the first 4 to 6 hours in accordance with the recommendations of the ad hoc ESPGHAN Committee (1).
Data collected included anthropometric measurements at admission, weight at short time intervals thereafter, number and characteristics of each stool passed during observation, fluid intake, and occurrence of vomiting. Stool samples were collected on entry and again at 48 hours. For most patients, an attempt was made to have a further stool sample at day 14 and day 30 after enrollment. Stool samples so collected were analyzed for rotavirus, adenovirus, Salmonella, Shigella, Campylobacter, Yersinia, Giardia, Cryptosporidium, and Amoeba.
The code was broken at the end of the investigation. Data analysis was performed at the coordinating center using the software for statistical analysis Epi-Info5, distributed by the Centers for Disease Control, (Atlanta, GA, U.S.A). We assessed, as end points, differences in the following parameters: percentage of treatment failures (defined as the need to resort to intravenous rehydration for any reason), duration of diarrhea after enrollment (defined as time in hours until last recorded fluid stool), progression of weight gain, percentage of children undergoing a course longer than 7 days in total, and, for inpatients, duration of hospital stay. Data are expressed as means ± SD, unless otherwise specified. Statistical analysis was performed using Student's t-test for unpaired variates and χ2 or Fisher's exact test, as appropriate.
Data at Study Entry
Three hundred twenty-three forms were sent to the coordinating center. Data from 36 forms were judged not amenable to evaluation, because they were incomplete and/or not compliant with the protocol. Consequently, 287 forms pertaining to 269 different patients were eventually available for evaluation. One hundred forty belonged to group A and 147 to group B patients. Figure 1 shows the number of patients who were enrolled in the various centers. Table 2 reports the most relevant clinical data at admission. There were no differences at study entry between the two groups in percentage of in-versus outpatients (percentage of inpatients was high in both groups), age, sex, weight, height, weight–height percentile, previous types of feeding, previous use of antibiotics, previous duration of diarrhea, characteristics of the stools, prevalence of fever and vomiting, overall condition, and degree of dehydration.
The results of the causative search performed at admission are reported in Table 3. Rotavirus was the single pathogen most commonly detected in both groups (32% in group A, 38% in group B). There were 21 patients in group A and 22 in group B (15% in each group) affected by invasive enteritis (Salmonella, Campylobacter, Yersinia, or Shigella). Forty-nine (35%) patients in group A and 35 (24%) in group B had no identifiable pathogen in their stools (a significant difference;P = 0.05). No significant difference of incidence was observed for any of the detected pathogens between the two groups.
In 11 patients from group A (7.8%) and 12 from group B (8.1%;P = NS) oral rehydration therapy failed, and the patients had to be rehydrated intravenously. All these patients had moderate-to-severe dehydration and eventually recovered. Reasons for the failure of therapy were similar in the two groups, with excessive vomiting the most common reason. Therapy failed in three patients from group A and one from group B because they refused to drink the ORS and were rehydrated intravenously. Data from these patients were excluded from further analysis.
Intake of Oral Rehydration Solution
The amount of ORS intake is reported in Table 4 for the study and the control groups. No significant difference was seen between the groups' intake during the rehydration phase (first 4 hours) or afterward.
Duration of Diarrhea
Table 5 reports the duration of diarrhea before and after entry into the study. Data are reported for the whole study sample (first pair of rows) and also relative to separate causative subsets. It is evident that intake of Lactobacillus GG–containing ORS resulted in a significant reduction of diarrhea afterward in the whole group (P = 0.03). This effect was mainly the result of the highly significant (P = 0.008) reduction of diarrhea seen in patients with rotavirus. In this subset of patients, who were significantly (P = 0.005) more frequently dehydrated than those with the remaining causes, diarrhea lasted approximately 20 hours less in the study group than in the control group. When considering other causes, it is apparent that children with invasive pathogen-induced enteritides (i.e., diarrhea caused by Salmonella, Shigella, Campylobacter, Yersinia, or Entamoeba) did not benefit from the intake of Lactobacillus GG–containing ORS. Of note, however, in the group of 99 children in whom no pathogen was identified, intake of Lactobacillus GG–containing ORS was associated with a reduced duration of diarrhea (P = 0.05).
To obtain a closer look at the effect of Lactobacillus GG on the diarrheal duration, patients were grouped according to 12-hour segments representing the duration of diarrhea (Fig. 2). It is evident that the data in the Lactobacillus GG–treated group were skewed to the left, and also it appears clear that a significant difference existed in the percentage of patients with prolonged course. If we consider the number of children who had a course longer than 132 hours after entry into the study (i.e., longer than 7 days from its onset), it is evident that only 4 (2.7%) of 147 patients in the Lactobacillus GG group versus 15 (10.7%) of 140 patients in the placebo group had a prolonged course (χ2 = 7.41;P = 0.0064). The relative risk of having diarrhea for more than a week was 3.94-fold (1.34<RR<11.58) higher in the placebo than in the Lactobacillus GG group.
Effect on the Watery Phase of Diarrhea
The average number of stools defined as watery is reported in Figure 3 for the 101 children with rotavirus enteritis. It is evident that the Lactobacillus GG–containing ORS significantly reduced the number of watery stools in patients affected by rotavirus. Additionally, as reported in Figure 4, a significant but smaller effect was also observed for the patients in whom no pathogen was identified. However, there was no effect on this parameter in the patients in whom diarrhea was due to invasive causes.
The patients receiving Lactobacillus GG in the ORS gained, during the first 24 hours, 220 ± 120 g (range, 8830 ± 2620 g to 9050 ± 2630 g). Those receiving only ORS gained, in the same period, 160 ± 200 g (range, 8750 ± 2790 g to 8910 ± 2680 g). Similar data were obtained when subdividing the patients according to cause of diarrhea. Thus, although children receiving Lactobacillus GG in ORS had a better average weight gain, it was not statistically significant.
Duration of Hospital Stay
The duration of hospital stay in hours is reported in Figure 5. Children receiving the ORS containing Lactobacillus GG stayed in the hospital for 78.8 ± 22.2 hours, whereas their counterparts were in the hospital for 96.3 ± 21.4 hours (P = 0.04). When considering the groups according to cause, it is evident that the clearest advantage was seen in the children affected by rotavirus. Hospital stay lasted 76.5 ± 15 hours in Lactobacillus GG–treated patients versus 97.9 ± 16.5 hours in control patients (P = 0.04). Although the mean duration of hospital stay also appeared to be shorter in the Lactobacillus GG–treated patients in the group of children with either an invasive pathogen or diarrhea of unknown origin, these differences were not statistically significant.
The use of lactic acid bacteria to treat human diseases is not a new concept (2,3). In fact, lactobacilli are among the most common bacterial species used to promote health and counteract intestinal infections. Among them, Lactobacillus rhamnosus strain GG (ATCC 53103) is by far the most widely investigated (4). This strain, with a capacity of transiently colonizing the human gastrointestinal tract that has been well established (5), has been shown to have a number of diverse, potentially beneficial, biologic effects and, in several clinical trials, to be effective in the prevention (6,7) and/or treatment of acute diarrheal disease in children (reviewed in [8,9]) and in adults (reviewed in ). However, although the effect of the probiotic is now considered well established in treating acute diarrheal disease due to rotavirus enteritis, the efficacy or inefficacy of this agent in ameliorating bacterial enteritis is not clear. Most clinical trials have been conducted in patients populations overwhelmingly composed of rotavirus-affected children (11–18). Furthermore, in reports in which a portion of the children studied were affected by likely bacterial pathogens (i.e., patients with bloody diarrhea and/or dysentery [19,20]) or in which a subset of patients were found to be affected by bacterial pathogens (18), the efficacy of the probiotic was doubtful. In our series, we confirmed in a large sample the substantial inefficacy of Lactobacillus GG in proven bacterial infectious diarrhea. In fact, in a series of 53 children with invasive pathogens (i.e., diarrhea caused by Salmonella, Shigella, Campylobacter, Yersinia, or Entamoeba), we found no difference in the duration of diarrhea between Lactobacillus GG–treated and placebo-treated groups. However, it is of interest to note that in the subset of patients in whom stools yielded no identifiable pathogens (a total of 99 children), the administration of Lactobacillus GG in the ORS induced a significant reduction of diarrheal duration. Because the Lactobacillus GG was shown to be effective in the patients with rotavirus diarrhea, we may then speculate that the success of the probiotic therapy in the patients with no identifiable pathogen may be explained by its efficacy against a pathogen of unidentified viral origin. Thus, it would appear that this particular strain of lactic acid bacteria is able to prevent and counteract the pathophysiological changes arising in the small bowel as a result of a viral infection but is less effective against those arising as a consequence of an invasive bacterial infection in the large intestine.
We can only speculate on the reason for this. Mack et al. (21) have recently presented evidence that in intestinal epithelial cells in vitro probiotic bacteria can enhance the expression of mRNA for two predominant mucins, MUC2 and MUC3. Such glycoproteins are known to have a protective role versus intestinal infections, and this mechanism may have a role in probiotic-induced protection from viral agents. Mucinase-producing bacteria, on the other hand, would effectively overcome this preventive mechanism.
In our experimental design, Lactobacillus GG was present in the ORS, a previously unreported way of administering the probiotic. We thought this innovative approach could guarantee an early colonization with the bacteria, thereby offering the most effective way of showing its efficacy. Additionally, because the intake of ORS clearly varies with the degree of dehydration, having the probiotic in the ORS would provide a means of delivering doses of the microorganism proportionate to the severity of the dehydration. Most patients did not continue to take appreciable amounts of ORS after the first 24 hours. In fact, on average, only approximately 300 ml in total was taken in after that time in both groups. Thus, intake of Lactobacillus GG can be assumed to have been 3 × 1010 CFU during the first 24 hours (approximately 1.5 × 1010 CFU during the first 4 hours), but only 1010 CFU during the entire course of the diarrheal episode.
Nevertheless, the efficacy of this approach in rotavirus-affected patients was similar to that previously reported in providing higher, more continuous doses 12,13,15,16). A recent report by Rautanen et al. (17) shows that early administration of Lactobacillus GG is effective, and that even a single early dose might be maximally effective, possibly as a result of a lasting colonization.
A result that in our opinion was of great interest is the dramatic reduction of the percentage of patients with a prolonged diarrheal episode. In the control population, more than 10% of the children had diarrhea for more than 7 days, whereas less than 3% of the treated children had such a prolonged course. The risk of having diarrhea for more than a week was found to be reduced almost four times in the Lactobacillus GG–treated group. These data show the capacity of the probiotic in helping prevent a protracted course, one of the most feared events in acute-onset diarrhea in children. Although we do not know the mechanism of prevention, it is tempting to speculate that the improved gut barrier function that Lactobacillus GG has shown in the animal (22), as well as its demonstrated anti-inflammatory effect in patients with food allergy (23) could have been contributing factors.
Finally, it is noteworthy that in our series of patients, mostly in hospitals, the length of hospital stay was markedly and significantly reduced by the use of Lactobacillus GG in ORS. This finding, mainly because of the clear effect on the duration of hospital stay for rotavirus patients, greatly adds to the benefits of this treatment by allowing a marked reduction in hospital costs as well as a diminished risk of hospital spread of rotavirus infection.
In summary, the data we present allow the following major conclusions to be drawn.
1. Lactobacillus GG can be safely administered in the ORS used in the initial rehydration of children with acute diarrhea of different origins.
2. This intervention results in a shorter duration of diarrhea. The effect is more evident in, but not limited to, rotavirus-positive patients.
3. Children who receive Lactobacillus GG have a markedly reduced chance of having diarrhea lasting more than a week than do their control counterparts.
4. Duration of hospital stay is almost 1 day less in patients receiving Lactobacillus GG in ORS.
In conclusion, we think that the current approach calling for use of hypotonic solutions (1) and early refeeding (24,25) in European children could be integrated with the use of Lactobacillus GG in the ORS to optimize the approach to infants and children who have acute-onset diarrhea.
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